Cross-feeding of intermediary and end-point metabolites is anticipated to play an important role in maintaining the stability of host-associate microbial communities. Despite such syntrophy-driven resilience, substantial variations in the intake of certain nutrients may lead to changes in the composition of gut microbial communities with uncertain consequences. Syntrophy and mutualism at the level of major carbon and energy sources have been documented, however little is known about metabolic interactions involving B-vitamins. Several B vitamins, such as B1 (thiamin), B2 (riboflavin), B3 (niacin), B5 (pantothenate) and B6 (pyridoxine) represent indispensable precursors in the biogenesis of essential coenzymes (TPP, FMN/FAD, NAD(P), CoA and PLP) respectively, in both the mammalian host and members of the gut microbiota. Our preliminary analyses using genome reconstruction indicate that persistence of auxotrophic strains spanning a large variety of species in the gut is strictly dependent on their ability to acquire vitamins originating from diet and/or prototrophic microbes via committed salvage pathways encoded in their genomes. Many species, especially within the dominant Bacteroides group are predicted to adopt an opportunistic lifestyle that combines de novo biosynthetic capabilities with salvage pathways including committed transporters for respective vitamins. The homeostasis of community structures based on essential coenzyme requirements is rigorously maintained via a variety of regulatory mechanisms that respond to changes in vitamin supply involving activation and suppression of de novo vs uptake/salvage pathways. We will use predictive bioinformatics to classify hundreds of human gut-colonizing microbial species and strains for B-vitamin proto/auxotrophy for seven B-group vitamins, precursors of universally essential coenzymes. We will apply a systems biology approach to evaluate transcriptomics and metabolomics and modeling to elucidate the impact of B-vitamin depletion and overabundance using in vitro co-culture and humanized gnotobiotic mice. These studies will elucidate the extent that resilience of microbial communities is driven by syntrophic metabolism of vitamins, precursors of essential co-factors, and whether changes in the dietary supply of such vitamins modulates the population structure and functional expression of gut microbial communities.